What provokes hepatocellular carcinoma?

There are many carcinogens that can cause tumors in animals in an experiment, but their role in the development of tumors in humans is not established. Such carcinogens include beta- dimethylaminoazobenzene (yellow paint), nitrosamines, aflatoxin and alkaloids of the ragwort.

The process of carcinogenesis from the moment of initiation to progression and development of clinical manifestations has many stages. The carcinogen binds to DNA with covalent bonds. The development of cancer depends on the ability of the host cells to repair DNA or from tolerance to carcinogenesis.

Relationship with cirrhosis of the liver

Cirrhosis, regardless of etiology, can be considered as a precancerous condition. Nodular hyperplasia progresses to cancer. Hepatocyte dysplasia, which is manifested by an increase in their size, nuclear polymorphism and the presence of multinucleated cells, affects groups of cells or whole nodes and may represent an intermediate stage of tumor development. Dysplasia is found in 60% of patients with hepatocellular carcinoma with cirrhosis and only 10% of patients with hepatocellular carcinoma without cirrhosis. In cirrhosis with high proliferative activity of hepatocytes, there is a higher risk of developing liver cancer. In addition, carcinogenesis can be associated with a genetic defect of a particular clone of cells.

Primary liver tumors

	Benign	Malignant
Hepatocellular	Adenoma	Hepatocellular carcinoma Fibrolamellar carcinoma Hepatoblastoma
Biliary	Adenoma Cystadenoma Papillomatosis	Cholangiocarcinoma Mixed hepatocholangiocellular carcinoma Cystadenocarcinoma
Mesodermal	Hemangioma	Angiosarcoma (hemangiendothelioma) Epithelioid haemangiendothelioma Sarcoma
Other	Mesenchymal hamartoma Lipoma Fibroma

The prevalence of primary liver cancer in the world

Geographical area	Frequency per 100,000 men per year
Group 1
Mozambique	98.2
China	17.0
South Africa	14.2
Hawaii	7.2
Nigeria	5.9
Singapore	5.5
Uganda	5.5

Group 2
Japan	4.6
Denmark	3.4
Group 3
England and Wales	3.0
USA	2.7
Chile	2.6
Sweden	2.6
Iceland	2.5
Jamaica	2.3
Puerto Rico	2.1
Colombia	2.0
Yugoslavia	1.9

In one study, which included 1073 patients with hepatocellular carcinoma, 658 (61.3%) also had cirrhosis. However, in 30% of African patients with hepatocellular carcinoma associated with hepatitis B, cirrhosis was absent. In the UK, approximately 30% of patients with hepatocellular carcinoma had no cirrhosis; life expectancy in this group of patients was relatively high.

There are significant geographical differences in the incidence of cancer among patients with cirrhosis of the liver. The frequency of this combination is especially high in South Africa and Indonesia, where cancer develops in more than 30% of patients with liver cirrhosis, while in India, the United Kingdom and North America, the incidence of cirrhosis and liver cancer is approximately 10-20%.

Communication with viruses

In viral liver damage, hepatocellular carcinoma develops against a background of chronic hepatitis and cirrhosis. Almost all patients with virus-associated hepatocellular carcinoma have concomitant cirrhosis. Necrosis and enhanced mitotic activity of hepatocytes contribute to the development of regeneration sites, which under certain conditions leads to hepatocyte dysplasia and cancer development. Although in most cases cancer is preceded by nodal regeneration and cirrhosis, the tumor can also occur without concomitant cirrhosis. In such cases, by analogy with chronic hepatitis of marmots (caused by a representative of the hepadnavirus family close to the hepatitis B virus) necrosis and inflammation are a necessary condition for the development of cancer.

Communication with the hepatitis B virus

According to world statistics, the prevalence of HBV carriage correlates with the incidence of hepatocellular carcinoma. The highest incidence of hepatocellular carcinoma is observed in countries with the highest number of HBV carriers. It was shown that the risk of hepatocellular carcinoma in HBV carriers is higher than in the population. In the development of hepatocellular carcinoma, the etiological role of other representatives of the family of hepadnaviruses, for example the virus of hepatitis marmots, has been proved. HBV DNA is found in the tissue of hepatocellular carcinoma.

Carcinogenesis is a multi-stage process in which both the virus and the host's body play a role. The end result of this process is disorganization and reorganization of DNA of hepatocytes. In hepatitis B, the virus is integrated into the chromosomal DNA of the host, but the molecular mechanism of the carcinogenic effect of HBV remains unclear. Integration is accompanied by chromosomal deletions and translocations, which affect the growth and differentiation of cells (insertion mutagenesis). However, deletions do not correspond to sites of embedding of viral DNA, and in 15% of cases the cancer of the viral genome sequence in the tumor tissue is not detected. It has been shown that the incorporation of HBV DNA into the host genome is not accompanied by either increased expression of any particular protooncogene or deletions of a specific region of the genome carrying a potential anti- oncogene. The nature of integration into the host cell genome is not constant, and the viral genome in different patients can integrate into different parts of the DNA of tumor cells.

X-antigen HBV is considered a transactivator that increases the rate of transcription of oncogenes.

The pre-S protein of the HBV coat can accumulate in toxic amounts sufficient for tumor development. Increased formation of pre-S-protein HBV in transgenic mice leads to severe inflammation of the liver and regeneration, followed by the development of tumors. Disordered regulation of HBV membrane protein expression may result from integration into host cell DNA.

Integration of HBV DNA leads to translocation of tumor suppressor genes on chromosome 17. Thus, tumor suppressor genes, for example p53 oncogene on chromosome 17, can play an important role in HBV-dependent hepatocarcinogenesis. The transforming growth factor a (TGF-a) is strongly expressed in 80% of patients with hepatocellular carcinoma. Perhaps he plays the role of cofactor. Histochemical studies show that TGF-a is localized in the same hepatocytes as HBsAg, but is absent in tumor cells.

The greatest value as a precancerous state is chronic hepatitis B with an outcome in cirrhosis. HBV leads to the development of cancer through integration, transactivation, mutations of tumor suppression genes and an increase in the level of TGF-a.

In carriers of HBsAg infected with HDV, hepatocellular carcinoma is less common, possibly due to the inhibitory effect on HDV.

Communication with the hepatitis C virus

There is a clear correlation between the incidence of HCV infection and the prevalence of hepatocellular carcinoma. In Japan, in the majority of patients with hepatocellular carcinoma, anti-HCV antibodies are detected in the serum and about half of the cases contain information on blood transfusions in the anamnesis. A clear correlation between the incidence of hepatocellular carcinoma and HCV is also observed in Italy, Spain, South Africa and the United States. The significance of HCV in the development of hepatocellular carcinoma is small in regions endemic for HBV infection, for example in Hong Kong. The results of epidemiological studies were influenced by the introduction of more accurate methods of diagnosis of HCV infection in practice than those of the first generation. So, the frequency of HCV infection in hepatocellular carcinoma in South Africa was not 46.1%, but 19.5%. In the United States, 43% of patients with hepatocellular carcinoma (HBsAg-negative) are diagnosed with anti-HCV using second-generation test systems or HCV-RNA in serum and liver. HCV appears to play a more important etiological role in the development of hepatocellular carcinoma than HBV. The incidence of hepatocellular carcinoma among patients with anti-HCV is 4 times higher than that of HBsAg carriers. The development of hepatocellular carcinoma in HCV infection does not depend on the genotype of the virus.

The low incidence of hepatocellular carcinoma due to HCV in the United States compared with Japan is associated with the age of the patients. Hepatocellular carcinoma develops only 10-29 years after infection. In Japan, HCV infection probably occurred mainly in early childhood when injected using non-sterile syringes. Americans were infected mainly in adulthood (drug addiction, blood transfusion), and hepatocellular carcinoma did not have time to develop during their lifetime.

Unlike HBV, HCV is an RNA-containing virus, does not have a reverse transcriptase enzyme, and is unable to integrate into the host cell genome. The development of hepatocellular carcinoma is unclear; apparently, it occurs against the background of cirrhotic transformation of the liver. However, in the tumor and the surrounding hepatic tissue of these patients, the HCV genome can be detected.

The interaction of HBV and HCV in the development of hepatocellular carcinoma is possible, as in patients with co-infection with HCV and HBV (HBsAg-positive) hepatocellular carcinoma develops more often than in patients with only anti-HCV.

Carriers of HCV, as well as carriers of HBV, should be regularly monitored for the presence of hepatocellular carcinoma by ultrasound (ultrasound) and determination of the level of alpha-fetoprotein (alpha-FP) in serum.

Connection with the use of alcohol

In Northern Europe and North America, the risk of developing primary hepatocellular carcinoma is four times higher among patients with alcoholism, especially the elderly. They always show signs of cirrhosis, and alcohol itself is not a hepatic carcinogen.

Alcohol can be a co-carcinogen of HBV. In patients with alcoholic cirrhosis complicated by hepatocellular carcinoma, hepatitis B markers are often detected. Alcohol-induced induction of enzymes can enhance the conversion of co-carcinogens into carcinogens. Alcohol can also stimulate carcinogenesis due to inhibition of immunity. Alcohol slows down the alkylation of DNA, mediated by carcinogens.

In hepatocellular carcinoma, patients with alcoholic cirrhosis sometimes have a built-in DNA of the degenerated hepatocyte HBV-DNA. However, hepatocellular carcinoma can develop in people with alcoholism and in the absence of HBV infection (current or previous).

Mycotoxins

The highest value of mycotoxins is aflatoxin, produced by mold fungus Aspergillus flavis. It gives a pronounced carcinogenic effect in rainbow trout, mice, guinea pigs and monkeys. There are interspecies differences in sensitivity to the carcinogenic effect of aflatoxin. Aflatoxin and other toxic substances found in molds can easily get into food, in particular peanuts (peanuts) and cereals, especially when stored in tropical conditions.

In different parts of Africa, a positive correlation was noted between the food content of aflatoxin and the incidence of hepatocellular carcinoma. Aflatoxin can act as a co-carcinogen in viral hepatitis B.

Studies in Mozambique, South Africa and China have identified mutations in the p53 tumor suppressor gene, which was associated with an increased content of aflatoxin in food. In the UK, where the likelihood of aflatoxin entering the food is low, these mutations were rare in patients with malignant liver tumors.

Race and gender

Evidence of the role of genetic predisposition to the development of hepatocellular carcinoma there.

Globally, hepatocellular carcinoma is 3 times more common in men than in women. This can be partly explained by the higher frequency of HBV carriage in men. It is possible to enhance the expression of androgen receptors and suppress estrogen receptors on tumor cells. The biological significance of this phenomenon is unknown.

The role of other factors

Hepatocellular carcinoma rarely complicates the course of autoimmune chronic hepatitis and cirrhosis of the liver.

The consumption of aflatoxin and the frequency of hepatocellular carcinoma

A country	Terrain	The consumption of aflatoxin, ng / kg per day	The frequency of HCC per 100 thousand people per year
Kenya	Highlands	3.5	1.2
Thailand	Sonkla	5.0	2.0
Swaziland	The steppe (high above sea level)	5.1	2.2
Kenya	Mountains of medium height	5.9	2.5
Swaziland	Steppe (average elevation above sea level)	8.9	3.8
Kenya	Low mountains	10.0	4.0
Swaziland	Upland of Lebombo	15.4	4.3
Thailand	Ratburi	45.6	6.0
Swaziland	The steppe (low above sea level)	43.1	9.2
Mozambique	Inhambane City	222.4	13.0

With Wilson's disease and primary biliary cirrhosis, hepatocellular carcinoma is also very rare.

Hepatocellular carcinoma is a common cause of death in patients with hemochromatosis. It often occurs with a deficiency of alpha ₁ -antitrypsin, type I glycogenosis and late cutaneous porphyria.

Hepatocellular carcinoma can be a complication of massive immunosuppressive therapy in patients with a transplanted kidney.

The clonorhoz may be complicated by hepatocellular carcinoma and cholangiocellular carcinoma.

The relationship between schistosomiasis and liver cancer is not established.

In Africa and Japan, hepatocellular carcinoma is combined with membranous obstruction of the inferior vena cava.